Rheumatoid arthritis is an autoimmune disease of unknown etiology that results in severe polyarticular inflammation and damage, and which affects about 1 % of the U.S. population. The disease has a strong genetic component which maps to the HLA-DR locus, with DR4 and DR1 being the most highly associated. Although much of the permanent damage to the joints is carried out by nonspecific myeloid cells of the immune system, the triggering event is likely to involve the activation of antigen-specific T cells, and is hypothesized to involve molecular mimicry between an exogenous microbial antigen and an autoantigen. This project will test predictions based on the theory that some autoreactive antigen-specific B cells are able to process their cognate self antigen and present cryptic determinants to latently autoreactive T cells thereby initiating the early events leading to rheumatoid arthritis. An essential component of the etiology of rheumatoid arthritis would, according to this theory, be determined by the character of the antibody response to infectious agents implicated in the triggering of the disease. The first hypothesis to be tested proposes that the antibody repertoire is subtly different between rheumatoid arthritis patients and healthy controls, and predicts that features of antibody V gene utilization in susceptible individuals can be identified which distinguish these individuals from non-susceptible individuals. The approach will be to determine the frequency of rearrangement of defined VH elements among pre B cells, preimmune B cells, B1 B cells, and memory B cells isolated from rheumatoid arthritis patients. The second major goal of this proposal will be to test the hypothesis that some autoantibody producing B cells from rheumatoid arthritis patients process and present cryptic determinants derived from the cognate self-antigen. Autoantibody-producing B cell lines will be generated and used as presenting cells. Epitope specificity of the B cells, as well as V-H and V-L utilization, will be determined. T cell lines responsive to peptides naturally processed by antigen-specific B cells will be generated. The specificity of the responding T cells will be assessed by their capacity to respond to synthetic peptides derived from the cognate antigen. This project will provide insight into possible mechanisms whereby the immune response to an infectious agent becomes misdirected toward self constituents. The results could have implications for immune intervention in the prevention of rheumatoid arthritis and other autoimmune diseases.